1. The Technical Field of the Invention
The present invention is related to compositions for pH dependent controlled release of active ingredients, especially pharmaceutical compositions. The composition is a compact consisting essentially of an active ingredient and a starch acetate dicarboxylate such as succinate. Methods for preparing the composition are also disclosed.
2. The Background of the Invention
Active compounds such as pharmaceuticals, natural health products, fertilizers, herbicides, insecticides, diagnostic reagents are usually not distributed as such, but in the form of more convenient compositions which make the distribution more feasible and allows the preparation of convenient dosage forms for different environmental conditions. Among these environmental conditions the acidity of the environment is an important factor. Pharmaceutical preparations are perhaps the most thoroughly studied compositions. Thus, the background for designing the present pH dependent controlled release compositions is discussed in more detail fundamentally based on the knowledge accumulated in studies with pharmaceutical preparations.
Pharmaceutical preparations typically comprise one or several excipients in addition to the active drug substance or substances. Excipients make the manufacturing of the pharmaceutical dosage forms more feasible and give them suitable physicochemical, biological and biopharmaceutical properties.
The administration of drugs to the human or animal body by way of controlled, sustained or delayed release from a dosage form located in gastrointestinal tract has long been an objective of the pharmaceutical industry. The controlled release dosage forms are used to optimize drug therapy, decrease frequency of dosing, and minimize undesirable side effects. It is generally known that the residence time of a drug in the stomach is largely unpredictable and it depends on the physiology of the individual and the amount and type of food which is taken with a meal. Thus, variations between different patients are particularly significant. On the other hand, the pH conditions in stomach and small intestine are markedly different. Numerous drugs are slightly soluble in acidic environment of stomach and they can be absorbed only when the surrounding pH is greater than 5, as it is in small intestine. Sustained or delayed release properties in dosage forms are primarily intended to extend the release of drug over an prolonged period of time to maintain therapeutic effective blood levels or to decrease the risks of side-effects. In addition, they are used to control the release of a drug at a predetermined point or predetermined points in the gastrointestinal tract. One among these effects is the enteric effect.
By definition, enteric dosage forms are those which remain practically intact in the stomach, but will disintegrate or dissolve and release the drug contents once the product reaches the small intestine. Their prime intention is to delay the release of drugs which are inactivated by the stomach contents, or may cause nausea or bleeding by irritation of the gastric mucosa, or are more preferentially absorbed into blood circulation from small intestine, or have local therapeutic effect in small intestine.
The most widely used technology for obtaining enteric effect is the coating of a compressed tablet by a polymeric film with enteric properties. The powder mixture consisting of drug substance(s) and several excipients is, firstly, mixed, most often also granulated and then compressed into tablets. These tablets are then coated in film coating processes. The preparation of coated products is a multistage process, including several separate mixing, granulation, tabletting and coating phases with numerous and complicated process variables.
Systems based on pH-sensitive polymers tend to be more reliable than those which are dependent of slow dissolution and erosion of the polymer. The most extensively used enteric polymer is cellulose acetate phthalate. Cellulose acetate phthalate films have good enteric properties, but they dissolve only over pH 6 and may thus delay drug release longer than desired. Said cellulose acetate phthalate films are also susceptible to hydrolytic breakdown on storage. Other enteric polymers include e.g. polyvinylacetate phthalate, hydroxy-propylmethylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymer, starch and amylose acetate phthalate, styrene maleic acid copolymer, and cellulose acetate succinate.
The enteric coatings are typically prepared by using either fludized bed or pan coating techniques. The application of enteric polymers is often accomplished by spraying organic solvent based solutions containing from 5 to 30% polymer. Although, water is the solvent of choice in pharmaceutical processes, even nowadays organic solvents are most often used in enteric coating processes. The evaporation of solvents and their possible harmful effects on tablet structure may, however, restrict the usability of the coating technique. Often plasticizers or some other components are mixed into the coating solution to improve film quality. Typical problems of enteric coating include tackiness, too porous structure or cracking of the films. Naturally, also all the other problems occasionally occurring in conventional film coating processes may exist in enteric coatings. The controlling and repeatability of the whole manufacturing chain is especially complicated. Often difficulties may arise due to breaking or inhomogeneity of a thin enteric coating film. As a consequence, the drug content can be released earlier than desired.
It is also known to prepare controlled release preparations by compressing formulations containing matrix forming excipients. Due to poor flowing, stickiness and smeary properties of enteric coating polymers, this method is very seldom used for preparation of enteric formulations. Direct compression of these substances without granulation in manufacturing scale is hardly possible.
Polymeric matrix formers with enteric properties, which can be processed by compressing, would be important in respect to time and energy saving as well as to better controlling of the whole manufacturing chain. The manufacture of enteric formulations using a compression process is in principle a simple and easily controllable process. If the direct compression process without granulation as a preprocess can be performed, it is possible to design even more simplified and better controllable manufacturing processes. Several disadvantageous process factors, e.g. granulation, drying of granules, usage of organic solvents, can then be avoided.
In patent application PCT/FI95/00331 corresponding to U.S. patent application Ser. No. 08/374,430 filed Jan. 19, 1995, claiming priority from the Finnish patent application Ser. No. 942686 filed on Jun. 7, 1994, a composition comprising compacts of starch acetates and active ingredients is disclosed. Said composition is characterized by its modifiable properties. In said patent application PCT/FI95/00331 it is also disclosed how to make different kinds of compacts, which are best suited for a certain purpose, e.g. controlled or sustained release. The release of the active ingredient from said composition is however not pH dependent.
As described above there is especially a need of pharmaceutical pH dependent controlled release compositions or entero-compositions such as compacts, e.g. tablets, granules and pellets. Even if the need for such a composition is especially prominent for pharmaceutical applications, such as drugs and natural health products, pH dependent controlled release compositions can be applied for designing compositions to be used as fertilizers, herbicides, diagnostic reagents, etc., as well.